Direct C–H difluoromethylation of heterocycles via organic photoredox catalysis

Abstract

The discovery of modern medicine relies on the sustainable development of synthetic methodologies to meet the needs associated with drug molecular design. Heterocycles containing difluoromethyl groups are an emerging but scarcely investigated class of organofluoro molecules with potential applications in pharmaceutical, agricultural and material science. Herein, we developed an organophotocatalytic direct difluoromethylation of heterocycles using O 2 as a green oxidant. The C-H oxidative difluoromethylation obviates the need for pre-functionalization of the substrates, metals and additives. The operationally straightforward method enriches the efficient synthesis of many difluoromethylated heterocycles in moderate to excellent yields. The direct difluoromethylation of pharmaceutical moleculars demonstrates the practicability of this methodology to late-stage drug development. Moreover, 2′-deoxy-5-difluoromethyluridine (F 2 TDR) exhibits promising activity against some cancer cell lines, indicating that the difluoromethylation methodology might provide assistance for drug discovery.

Visible‐Light Photoredox Catalyzed C−N Coupling of Quinoxaline‐2(1H)‐ones with Azoles without External Photosensitizer

“…In the absence of visible light or under white light irradiation, no desired product 3 aa was observed (Table 1, entries 16 and 17). Subsequently, several photocatalysts, including Ru(bpy) 2 Cl 2 , methylene blue, fluorescein, rose bengal and eosin Y, were examined to improve the efficiency of the [c] 390-395 nm CH 3 CN -82 26 [d] 390-395 nm CH 3 CN -Trace 27 [e] 390-395 nm CH 3 CN -71 28 [f] 390-395 nm CH 3 CN -84 29 [g] 390-395 nm CH 3 CN -73 30 [h] 390 Cl 2 ) = 0.77 V versus SCE in acetonitrile, [26] E p/2 (methylene blue) = 1.60 V versus SCE in acetonitrile, [27] E p/2 (fluorescein) = 0.78 V versus SCE in acetonitrile, [28] E p/2 (rose bengal) = 0.99 V versus SCE in acetonitrile, [29] E p/2 (eosin Y) = 0.79 V versus SCE in acetonitrile]. [30] So, the above mentioned photocatalysts cannot react with substrate 1 a (E p/2 = 1.84 V versus SCE in acetonitrile) or 2 a (E p/2 = 1.81 V versus SCE in acetonitrile) via an electron transfer process.…”

Recent Advances in Photocatalytic Functionalization of Quinoxalin‐2‐ones

“…In early 2020, Li and collaborators reported a methodology to incorporate difluoromethyl groups to quinoxalin-2-ones and other aromatic heterocycles. [51] The CF 2 H group is an important fluorinated functional group that, recently, have received huge attention in medicinal chemistry and pharmaceutical industry. This fluorinated group has been used as a lipophilic hydrogenbond donor, and as isoster of a thiol, a hydroxyl, and an amide, bringing new opportunities for drug development.…”

“…In early 2020, Li and collaborators reported a methodology to incorporate difluoromethyl groups to quinoxalin‐2‐ones and other aromatic heterocycles . The CF 2 H group is an important fluorinated functional group that, recently, have received huge attention in medicinal chemistry and pharmaceutical industry.…”

Dual-modal Light-harvesting Microfluidic System via Simultaneous Up- and Down-Conversions for Enhanced Flow Photocatalysis

“…In particular, photoredox catalysis using various organic photocatalysts is inexpensive and exhibits low toxicity. [1][2][3] However, photochemical organic transformations often occur at limited penetration distances due to the utilization of light through absorbing media. Consequently, the transformation e ciency may be low in conventional bulk reactors.…”

“…Co. Ltd., China) as an NIR light source. The solution of starting reagent (0.075 M) mixed with RB (5 mol%) in acetonitrile, reactant, and H 2 O (1:0.8:0.2 v/v/v) was fed into the fabricated micro uidic devices using a KD Scienti c Legato 180 syringe pump (Holliston, MA, USA) 1. H NMR (300, 400, or 500 MHz) and13 C NMR (125 MHz) spectra were recorded on a Bruker AVANCE III HD 300, 400 or 500-MHz NMR spectrometer in CDCl 3 .…”